In recent years, mouse and human iPS cells have been established one after another. Takahashi and Yamanaka (1) induced iPS cells by introducing the Oct3/4, Sox2, Klf4 and c-Myc genes into fibroblasts derived from a reporter mouse wherein the neomycin resistance gene is knocked-in into the Fbx15 locus, and forcing the cells to express the genes. Okita et al. (2) succeeded in establishing iPS cells (Nanog iPS cells) that show almost the same gene expression and epigenetic modification as those in embryonic stem (ES) cells by producing a transgenic mouse wherein the green fluorescent protein (GFP) and puromycin-resistance genes are integrated into the locus of Nanog, whose expression is more localized in pluripotent cells than Fbx15 expression, forcing the fibroblasts derived from the mouse to express the above-mentioned 4 genes, and selecting puromycin-resistant and GFP-positive cells. Similar results were confirmed by other groups (3, 4). Thereafter, it was revealed that iPS cells could also be produced with 3 factors other than the c-Myc gene (5).
Furthermore, Takahashi et al. (6) succeeded in establishing iPS cells by introducing the same 4 genes as those used in the mouse into human skin fibroblasts. On the other hand, a group of Yu et al. (7) produced human iPS cells using Nanog and Lin28 in place of Klf4 and c-Myc. Park et al. (8) produced human iPS cells using the TERT and the SV40 large T antigen, which are known as the human cell immortalizing genes, in addition to the 4 factors Oct3/4, Sox2, Klf4 and c-Myc. Hence, it has been demonstrated that iPS cells comparable to ES cells in pluripotency can be produced in both humans and mice by introducing defined factors into somatic cells.
However, the efficiency of iPS cell establishment is low at less than 1%. Especially, a problem of extremely low efficiency of iPS cell establishment occurs when they are produced by introducing 3 factors (Oct3/4, Sox2 and Klf4) is other than c-Myc, which is feared to cause tumorigenesis in tissues or individuals differentiated from iPS cells, into somatic cells.
p38 belongs to the MAP kinase (Mitogen-activated protein kinase) family and the p38 signal transduction pathway is known to be involved in environmental stress, UV light, apoptosis and inflammatory responses. In recent years, moreover, activation of p38 in cancer has also been reported (9). However, its relationship with nucleus reprogramming is not known well.